In particular, the present invention relates to a group of molecules suitable for selectively reducing the inflammation that develops at the level of the duodenum and of the proximal jejunum in individuals suffering from the celiac disease.
The celiac disease, also known as celiac sprue, is a quite common autoimmune disease having genetic, immunological and environmental components.
At the basis of the celiac disease is a permanent intolerance to gliadin, a protein fraction of gluten contained in wheat, or to similar protein fractions soluble in alcohol (prolamines), contained in barley, rye, spelt, kamut and in other minor cereals.
In the celiac disease, the mucosa of the small intestine becomes damaged subsequent to the exposure to the antigen (gliadin). In the disease, the intestinal villi tend to become flattened and the crypts hyper-proliferate for compensation, the enterocytes take up a cubic rather than cylindrical shape and the number of lymphocytes in the intestinal lumen increases.
The symptomatology that accompanies the disease is very complex and not limited to the gastroenteric area. In fact, the typical symptoms at a local level that commonly comprise diarrhoea, abdominal ache with possible bleeding, lactose intolerance, are accompanied by an extra-intestinal symptomatology that may comprise aphthous stomatitis, bone pain, progressive weight loss with weakening. Moreover, in the cases of untreated or refractory celiac disease, there are risks of developing gastrointestinal lymphoma or carcinoma as well.
Not infrequently, moreover, the celiac disease subject may exhibit a deficit of iron or ferritin, along with possible deficiency of vitamins A, B12, D, E, K and folic acid, caused by the intestinal malabsorption. Moreover, the continuous loss of fats through defecation may cause a calcium deficiency and develop two possible complications, one at a renal level with formation of calcium oxalate calculi and the other at a bone level, with the development of osteomalacia, a pathology that causes bone weakening.
In a percentage of individuals, the disease may even be totally or partially asymptomatic, that is, exhibit no clear symptoms or be in a latent form, ready to break out following particular events.
Since the antigen that triggers the disease is known, it is possible to obtain a full remission of the correlated symptoms by simply avoiding the intake of gluten-containing food.
Since the disease control is based on the adherence to a strict diet, it is not sufficient to avoid the intake of food that as everybody knows contains gluten, such as pasta, bread, barley, spelt, but it is also essential to avoid taking food that may contain it in small amounts, for example as a thickening or structuring agent, or as traces lost in the processing.
For example, the celiac disease patient must avoid taking espresso coffee at the bar (this may be contaminated with barley), spices, icing sugar, some pharmaceutical preparations and pay attention also to the glue found, for example, in stamps and mail envelopes.
The diet of celiac disease patients can, in any case, be sufficiently varied and well balanced eating only food such as rice, corn, buckwheat, millet, amaranthus, meat, fish, vegetables, fruit, cheese and legumes.
According to some recent studies there is a critical threshold of 20 ppm gluten per food, beyond which the food contents becomes toxic for the celiac disease subject. The Codex Alimentarius envisages two types of thresholds for labelling food as gluten-free. A first one is set at 100 ppmand relates to “detoxified” food that among the starting materials also contains toxic cereal derivatives, such as for example wheat starch, and a 20 ppm threshold for food free from ingredients derived from toxic cereals.
The strict observance of the diet and of some basic behaviour rules prevents the onset of new symptoms and generally causes, in a more or less marked manner according to the individual response, the remission of the symptoms developed. The diet, however, must be observed for the entire life despite the lack of symptoms or even the lack of antibodies in serum.
Besides the diet, however, no form of treatment is currently available for celiac disease subjects, in particular there are no products that may restrain the inflammatory symptoms that accompany the ingestion, even accidental, of gluten-containing food.
The few methods of therapeutic intervention attempted so far did not lead to the achievement of significant results.
Since the disease is strictly correlated to some genes that code for the antigens of human leukocytes (HLA) DQ2 and DQ8, some forms of treatments aimed at inhibiting the bond of the peptides of gluten at HLA DQ2/DQ8. In particular, some HLA-DQ2-blocking compounds have been tested but without achieving significant results.
The use of zonulin antagonists, a protein involved in the regulation of the intercellular junctions of the small intestine, the expression whereof increases during the acute stage of the disease, has been described in literature for the treatment of the celiac syndrome. However, no drug based on this protein is currently available on the market.
Moreover, anti-inflammatory drugs for topical mucosal use have found no application to date other than the treatment of chronic intestinal inflammatory forms, localised at the level of the colon, the distal tract of the intestine. For this reason, the preparations available on the market for treating the Crohn disease and the ulcerative colitis are sold as suppositories or solutions for rectal use. On the contrary, when these preparations are intended for oral administration, they are formulated for the delayed release of the active principle so as to pass intact along the digestive tube and allow the release of the active principle at the level of the colon only.
These drugs therefore have no effect on the duodenal portion of the intestine where the inflammatory focus in the celiac disease is localised.
Therefore, a clinical need is currently felt of having substances provided with pharmacological activity which should allow restraining the immuno-inflammatory based symptoms that develop at the level of the duodenal mucosa of the small intestine in the celiac disease.